A major challenge in gastrointestinal research today is to gain a better understanding of the underlying molecular mechanisms for maintenance of the exocrine pancreas and small bowel mucosa. Acute pancreatitis (AP) is a complex and poorly understood disease. Severe acute hemorrhagic or necrotizing pancreatitis in humans results in an exceptionally high morbidity and mortality. Despite the abundance of pancreatitis patients, underlying molecular mechanisms that control the severity of an AP are not known. Likewise, a deficiency in appropriate intestinal regeneration or adaptation following mucosal disease or injury can be clinically relevant. The specialized epithelial cells of the small bowel mucosa constitute an essential organ for nutrient absorption, immune function and regulation of fluid and electrolyte balance. Disruption of the integrity of the intestinal mucosa either through inflammation, infiltration, surgical resection or ischemia results in severe malabsorption and ultimately in clinical malnutrition requiring total parenteral nutritional support. The long term objectives of the proposed work are to understand the roles gastrointestinal (GI) hormones play in the homeostasis of the pancreas, and in controlling GI epithelial restitution and regrowth. The Specific Aims of this research proposal are: 1) to determine the role of gastrointestinal hormones in the regulation of pancreatic apoptosis and regeneration in experimental models of acute pancreatitis; and, 2) to determine the role of gastrointestinal hormones in the regulation of adaptive hyperplasia of the gut. The proposed studies are designed to precisely define, in a systematic fashion, the components of GI hormone-linked intracellular transduction pathways involved in the regulation of pancreatic apoptosis and regeneration in experimental models of AP; and, the proliferation of GI mucosa associated with adaptive hyperplasia of the gut. In order to accomplish these aims, we will investigate molecular pathways of acinar cell proliferation and apoptosis in three different models of experimental AP, and the intracellular signal transduction pathways mediating the regulation of neurotensin gene expression by insulin-like growth factor-I (IGF-I) and the enhancement of glucagon-like peptide-2 (GLP-2)- stimulated mucosal proliferation by neurotensin. These studies will provide a foundation for the development of innovative therapeutic strategies designed to exploit the unique biological activities of GI hormones on the exocrine pancreas and intestinal mucosa.